Field of the invention
[0001] The present invention relates to a process for the preparation of (3R,3aS,6aR)-hexahydrofuro
[2,3-b] furan-3-yl (1S,2R)-3-[[(4-aminophenyl) sulfonyl] (isobutyl) amino]-1-benzyl-2-hydroxypropylcarbamate
as well as intermediates for use in said processes. More in particular the invention
relates to processes for the preparation of (3R,3aS,6aR)-hexahydrofuro [2,3-b] furan-3-yl
(1S,2R)-3-[[(4-aminophenyl) sulfonyl] (isobutyl) amino]-1-benzyl-2-hydroxypropylcarbamate
which make use of 4-amino-N-[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl]-N-isobutylbenzene
sulfonamide intermediate, and which are processes amenable to industrial scaling up.
Background
[0002] The virus causing the acquired immunodeficiency syndrome (AIDS) is known by different
names, including T-lymphocyte virus III (HTLV-III) or lymphadenopathy-associated virus
(LAV) or AIDS-related virus (ARV) or human immunodeficiency virus (HIV). Up until
now, two distinct families have been identified, i.e. HIV-1 and HIV-2. Hereinafter,
HIV will be used to generically denote these viruses.
[0003] One of the critical pathways in a retroviral life cycle is the processing of polyprotein
precursors by retroviral protease. For instance, during the replication cycle of the
HIV virus, gag and gag-pol gene transcription products are translated as proteins,
which are subsequently processed by a virally encoded protease to yield viral enzymes
and structural proteins of the virus core. Most commonly, the gag precursor proteins
are processed into the core proteins and the pol precursor proteins are processed
into the viral enzymes, e.g., reverse transcriptase and retroviral protease. Correct
processing of the precursor proteins by the retroviral protease is necessary for the
assembly of infectious virions, thus making the retroviral protease an attractive
target for antiviral therapy. In particular for HIV treatment, the HIV protease is
an attractive target.
[0004] Several protease inhibitors are on the market or are being developed. Hydroxyethylamino
sulfonamide HIV protease inhibitors, for example 4-aminobenzene hydroxyethylamino
sulfonamides, have been described to have favourable pharmacological and pharmacokinetic
properties against wild-type and mutant HIV virus. Amprenavir is a commercially available
exponent of this 4-aminobenzene hydroxyethylamino sulfonamide class of protease inhibitors.
A process for the synthesis of amprenavir is described in
WO99/48885 (Glaxo Group Ltd.).
[0005] 4-aminobenzene hydroxyethylamino sulfonamides may also be prepared according to the
procedures described in
EP 715618,
WO 99/67417,
US 6,248,775, and in
Bioorganic and Chemistry Letters, Vol. 8, pp.687-690, 1998, "Potent HIV protease inhibitors incorporating high-affinity P
2-ligands and (
R)-(hydroxyethylamino) sulfonamide isostere", all of which are incorporated herein
by reference. In particular, (3R,3aS,6aR)-hexahydrofuro [2,3-b] furan-3-yl (1S,2R)-3-[[(4-aminophenyl)
sulfonyl] (isobutyl) amino]-1-benzyl-2-hydroxypropylcarbamate, herein referred to
as compound of formula (6), and methods for its preparation may be found disclosed
in
WO99/67417 (USA, The Secretary, Dpt. of Health and Human Services), and in
PCT/EP03/50176 (Tibotec N.V.).
[0006] WO03/057665 (Ajinomoto KK) relates to a process for producing crystals of benzenesulfonamide
derivatives. In particular, it provides a crystallization for (2R,3 S)-N-(3-amino-2-hydroxy-4-phenylbutyl)-N-isobutyl-4-amino-benzenesulfonamide,
which is an intermediate of interest for the preparation of (3R,3aS,6aR)-hexahydrofuro
[2,3-b] furan-3-yl (1S,2R)-3-[[(4-aminophenyl) sulfonyl] (isobutyl) amino]-1-benzyl-2-hydroxypropylcarbamate.
This intermediate of interest is obtained according to the disclosure by departing
from a (2S,3S)-3-benzyloxycarbonylamino-1,2-epoxy-4-phenylbutane, to which isobutylamine
is reacted, followed by coupling of p-nitrobenzenesulfonylchloride to yield (2R,3S)-N-(3-benzyloxycarbonylamino-2-hydroxy-4-phenylbutyl)-N-isobutyl-4-nitrobenzenesulfonamide,
which is simultaneously reduced and deprotected to obtain the intermediate of interest.
In particular, the route employs a benzyloxycarbonyl (Cbz or Z) as the amino protecting
group of the core molecule. It is observed that the simultaneous reduction of the
nitro moiety and Cbz deprotection in (2R,3S)-N-(3-benzyloxycarbonylamino-2-hydroxy-4-phenylbutyl)-N-isobutyl-4-nitrobenzenesulfonamide
results in a highly exothermic reaction. Exothermic reactions, if possible, should
be avoided or limited to its minimum extent, as they are more difficult for controlling
reaction temperatures, i.e. when the reaction temperature would be too low, the reaction
rate is small and a long time is required; when the reaction temperature woud be too
high, the reaction rate is too large and insufficient mixing occurs, inviting nonuniform
reaction, deterioration (burning) of the product formed, or unwanted side reactions
may take place with the result that product selectivity is decreased. On the other
hand, it is also observed that the catalytic reduction disclosed in
WO03/057665 does not include an acid treatment. In the absence of an acid treatment, it is expected
that the catalyst employed during reduction and Cbz deprotection will be poisoned
with the sulfur from p-nitrobenzenesulfonylchloride. A poisoned catalyst will inevitably
result into the appearance of side-products thus decreasing product selectivity.
[0007] In order for a chemical route to be suitable for industrial scale, it should produce
compounds in acceptable yields and purity while being easy and simple to carry out,
as well as cost-effective. As such, there has been found a new process for the synthesis
of compound of formula (6) which is amenable for industrial scale.
[0008] In particular, the present invention provides a convenient process for the production
of compound of formula (6) and intermediates, addition salts, polymorphic and/or pseudopolymorphic
forms thereof at industrial scales. More in particular, the present invention concerns
a process for preparing a compound of formula (6) as defined in claim 1. Preferred
embodiments are defined in claims 2 to 14. The present invention encompasses a suitable
route for the synthesis of compound of formula (6) which further benefits from an
improved and cost-effective crystallization of (2R,3 S)-N-(3-amino-2-hydroxy-4-phenylbutyl)-N-isobutyl-4-amino-benzenesulfonamide
with acceptable purities and yields. Even more in particular, the present invention
presents separate reduction and deprotection reactions encompassing an acid treatment,
all resulting in a more controllable, selective and cost-effective process.
[0009] In one embodiment, the present invention provides an improved crystrallization employing
pH and concentration controls in defined ranges, while the crystallization by
WO03/057665 only makes mention of heating the solution in polar solvent in order to improve the
yield, or heating the solution (30-80°C) in order to dissolve the crystals present
in the polar solvent solution in order to improve purification.
[0010] The present invention has the further advantage of using commercially available starting
material, such as a 1-oxiranyl-2-phenyl-ethyl-carbamic acid tert-butyl ester. Further,
the precursor of compound of formula (6), i.e. (2R,3S)-N-(3-amino-2-hydroxy-4-phenylbutyl)-N-isobutyl-4-amino-benzenesulfonamide
or compound of formula (5), may be produced as a one-pot procedure which results in
an efficient utilization of the reactor and the omission of intermediate purification
steps. The reagents further used in said process are safe and available in bulk. Furthermore,
each step of said method is performed at controllable conditions and provides with
the desired compound in optimal yields. Moreover, each step of said process is performed
5stereoselectively, which allows the synthesis of pure stereoisomeric forms of the
desired compounds.
[0011] Other objects and advantages of the present invention will become apparent from the
following detailed description taken in conjunction with the accompanying examples.
[0012] EP0754669 (Kaneka Corporation) describes processes for producing alpha-halo ketones, alpha-halohydrins
and epoxides;
EP1029856 (Kaneka Corp.) discloses a process for the preparation of (2R,3S)-3-amino-1,2-oxirane;
and
EP1067125 also by Kaneka Corporation relates to a process for the preparation of threo-1,2-epoxy-3-amino-4-phenylbutane.
EP774453 (Ajinomoto Co., Inc.) describes a p
rocess for producing 3-amino-2-oxo-1-halogenopropane derivatives. In WO01/12599 (Samchully Pharm Co. Ltd.) there is described new ethylaziridine derivatives and
their preparation methods.
WO01/46120 (Aerojet Fine Chemicals LLC) discloses an improved preparation of 2S,3S-N-isobutyl-N-(2-hydroxy-3-amino-4-phenylbutyl)-p-nitrobenzenesulfonylamide
hydrochloride and other derivatives of 2-hydroxy-1,3-diamines. In
WO96/28418 (G. D. Searle & Co., Inc.) there are disclosed sulfonylalkanoylamino hydroxyethylamino
sulfonamide retroviral protease inhibitors.
WO94/04492 (G. D. Searle & Co., Inc.) discloses alpha- and beta-amino acid hydroxyethylamino
sulfonamides useful as retroviral protease inhibitors.
WO97/21685 (Abbott) discloses the preparation of peptide analogues as retroviral protease inhibitors.
WO94/05639 (Vertex Pharmaceuticals) describes sulfonamide inhibitors of HIV-1 aspartyl protease.
Detailed description of the invention
[0013] The present invention relates to a process for the preparation of compound of formula
(6), addition salts, polymorphic and/or pseudopolymorphic forms thereof;
which comprises:
- (i) introducing an isobutylamino group in compound of formula (1');
to obtain compound of formula (2');
- (ii) introducing a p-nitrophenylsulfonyl group into compound of formula (2') to obtain
compound of formula (3');
- (iii) reducing the nitro moiety of compound of formula (3') to obtain compound of
formula (4');
- (iv) deprotecting compound of formula (4') to obtain compound of formula (5);
coupling compound of formula (5) with (3R,3aS,6aR)-hexahydrofuro [2,3-b] furan-3-yl
derivate, obtained by activating (3R,3aS,6aR)-hexahydrofuro [2,3-b] furan-3-ol or
precursor thereof by carbamoylation with a coupling agent to obtain compound of formula
(6) wherein said precursor of (3R, 3aS, 6aR)-hexahydrofuro [2, 3-b] furan-3-ol comprises
compounds wherein the oxygen of the alcohol function is protected with O-protecting
groups, selected from t-butyl ether, acetates, benzyl groups, benzyl ethers, allyls,
silyl protecting groups, alkoxyalkyl groups tetrahydropyranyl.
[0014] The present invention thus involves processes for the preparation of compound of
formula (6), addition salts, polymorphic and/or pseudopolymorphic forms thereof; through
the intermediate of formula (5)
[0015] Preferably, compound of formula (5) is crystallized as a free-base. Alternatively,
compound of formula (5) is crystallized as a salt with strong acids such as hydrochloric
acid, hydrobromic acid, methanesulfonic acid, sulfuric acid, oxalic acid, citric acid,
and the like. Crystallization of compound of formula (5) improves its purity and yield,
both beneficial factors for the production of compound of formula (6). Alternatively,
compound of formula (5) may be crystallized as a polymorphic and/or pseudopolymorphic
form thereof.
[0016] Preferably, compound of formula (6) is crystallized as a pseudopolymorphic form,
preferably as an alcoholate, more preferably as an ethanolate.
[0017] The term "C
1-6alkyl" as a group or part of a group defines straight and branched chained saturated
hydrocarbon radicals having from 1 to 6 carbon atoms such as methyl, ethyl, isopropyl,
butyl, pentyl, hexyl, 2-methylbutyl, 3-methylpentyl and the like.
[0018] Compound of formula (1') are commercially available and may be prepared in several
ways available in the literature, for example as described in
WO95/06030 (Searle & Co.), as described by Kaneka Corporation in
EP0754669 EP1029856 and
EP1067125, and as disclosed by Ajinomoto KK in
EP1081133 and
EP1215209.
Compound of formula (2')
[0019] Compound of formula (1') is subjected to an amination on the epoxide to render compound
of formula (2').
[0020] The term "amination" as used herein refers to a process in which a primary amine,
isobutylamine, is introduced into the organic molecule of formula (1'). Amination
of compound of formula (1') may be accomplished in several ways available in the literature,
for example as described in
WO95/06030, which is incorporated herein by reference.
[0021] According to the invention, compound of formula (1') is reacted with isobutylamine
to yield compound of formula (2').
[0023] The amination agent, isobutylamine, may function as well as a solvent, in which case,
an excess of isobutylamine will be added. In other embodiments, the amination process
is performed in the presence of one or more solvents other than isobutylamine. In
a preferred embodiment, said solvents are used in the work-up of compound of formula
(2').
[0024] Suitable solvents include protic, non-protic and dipolar aprotic organic solvents
such as, for example, those wherein the solvent is an alcohol, such as methanol, ethanol,
isopropanol, n-butanol, t-butanol, and the like; ketones such as acetone; ethers such
as diethyl ether, tetrahydrofuran, dioxane and the like; esters such as ethyl acetate;
amines such as triethylamine; amides such as N,N-dimethylformamide, or dimethylacetamide;
chlorinated solvents such as dichloromethane and other solvents such as toluene, dimethyl
sulfoxide, acetonitrile, and mixtures thereof. A preferred solvent is toluene.
[0025] Conveniently the reaction can be conducted over a wide range of temperatures, e.g.,
from about -20°C to about 200°C, but is preferably, although not necessarily, conducted
at a temperature at which the solvent refluxes, i.e. between 40°C and 100°C, more
preferably between 60°C and 90°C.
[0026] Suitably the ratios of equivalents between the compound of formula (1') and the amination
agent may range from 1:1 to 1:99, respectively. Preferably, the ratio of equivalents
between the compound of formula (2') and the amination agent is from 1:5 to 1:20,
more preferably the ratio is from 1:10 to 1:15.
[0027] In an embodiment of the invention, the amination reaction is carried out in the presence
of about 15 equivalents of isobutylamine, using toluene as solvent, and heating to
reflux at about 79°C.
Compound of formula (3')
[0028] Compound of formula (3') is prepared by introducing the sulfonyl moiety, p-nitrobenzene-SO
2, into the intermediate of formula (2').
[0029] As such, compound of formula (2') will react with a sulfonylating agent to transform
into compound of formula (3').
[0030] The term "sulfonylation" as used herein refers to a process in which p-nitrobenzene-sulfonyl
moeity is introduced into the organic molecule of formula (2'). The term "sulfonation"
as used herein refers to a process in which a sulfonylating agent is prepared. The
term "sulfonylating agent" is referred to p-nitrobenzene-sulfonyl derivatives, such
as p-nitrobenzenesulfonyl haloderivatives.
[0031] The sulfonylating agents, and in particular p-nitrobenzenesulfonyl haloderivatives,
can be prepared by the oxidation of thiols to sulfonyl chlorides using chlorine in
the presence of water under carefully controlled conditions. Additionally, sulfonic
acids may be converted to sulfonyl halides using reagents such as PCl
5, and also to anhydrides using suitable dehydrating reagents. The sulfonic acids may
in turn be prepared using procedures well known in the art. Such sulfonic acids are
also commercially available. Sulfonylating agents may as well be prepared by the sulfonation
procedures described in "
Sulfonation and Related Reactions", by E. E. Gilbert, R. E. Krieger Publishing Co.
Huntington, N.Y. (1977), "
Mechanistic Aspects of Aromatic Sulfonation and Desulfonation", by H. Cerfontain,
Interscience Publishers, NY (1968), and in
US6455738, "Process for the sulfonation of an aromatic compound", all incorporated herein by
reference.
[0032] The treatment of compound of formula (2') with the sulfonylating agent can be carried
out in the presence of a solvent under heating, approximately between 25° to 250°
C, preferably between 70° and 100°C and agitation. After the sulfonylation, any remaining
sulfonylating agent or salts are preferably, although not necessarily, removed from
the reaction mixture. This removal can be accomplished by repeated washing with water,
change of pH, separation of organic and aqueous phases, ultrafiltration, reverse osmosis,
centrifugation, and/or filtration or the like.
[0033] The compound having formula (3') are prepared by reacting a sulfonylating agent with
intermediate of formula (2') in suitable solvents under alkaline conditions. Suitable
alkaline conditions include conventional non-nucleophilic inorganic or organic bases
and/or acid scavengers. Conventional non-nucleophilic inorganic or organic bases include,
for example, hydrides, hydroxides, amides, alcoholates, acetates, carbonates, or hydrogen
carbonates of alkaline earth metals or alkali metal hydrides such as, for example,
sodium hydride, potassium hydride or calcium hydride, and metal amides, such as sodium
amide, potassium amide, lithium diisopropylamide or potassium hexamethyldisilazide,
and metal alkanes such as sodium methylate, sodium ethylate, potassium tert-butylate,
sodium hydroxide, potassium hydroxide, ammonium hydroxide, sodium acetate, potassium
acetate, calcium acetate, ammonium acetate, sodium carbonate, sodium bicarbonate,
potassium carbonate, potassium bicarbonate, cesium carbonate, potassium hydrogen carbonate,
sodium hydrogen carbonate, or ammonium carbonate, and also basic organic nitrogen
compounds such as, trialkylamines, like trimethylamine, triethylamine, tributylamine,
N,N-dimethylaniline, N,N- dimethyl-benzylamine, N,N-diisopropylethylamine, pyridine,
1,4-diazabicyclo-[2.2.2]-octane (DABCO), 1,5-diazabicyclo[4.3.0]-non-5-ene (DBN),
or 1,8-diazabicyclo[5.4.0]-undec-7-ene (DBU), or an excess of an appropriate piperidine
compound may be used. Preferably triethylamine is used.
[0034] Suitable solvents have been illustrated in the preparation of formula (2') above,
being inert solvents preferred, such as for example toluene, ethylacetate, methylene
chloride, dichloromethane, and tetrahydrofuran.
[0035] Conveniently, the ratios of equivalents, calculated from compound of formula (1'),
and the sulfonylating agent range from 1:1 to 1:3, respectively. Preferably, the ratio
of equivalents between the compound of formula (1') and the sulfonylating agent is
from 1:1 to 1:2, more preferably the ratio is around 1:1.15.
Compound of formula (4')
[0036] Compound of formula (4') are obtained by reducing the nitro moiety of intermediate
of formula (3') respectively with a reducing agent, optionally under a hydrogen atmosphere.
[0037] Reducing agents suitable for reduction of the nitro moiety are metallic reducing
reagents such as borane complexes, diborane, sodium borohydride, lithium borohydride,
sodium borohydride-LiCl, aluminum lithium hydride, or diisobutylaluminium hydride;
metals such as iron, zinc, tin and the like; and transition metals such as palladium-carbon,
platinum oxide, Raney-nickel, rhodium, ruthenium and the like. When catalytic reduction
is applied, ammonium formate, sodium dihydrogenphosphate, hydrazine may be used as
the hydrogen source.
[0038] Solvents suitable for the reduction of the nitro moiety may be selected from water,
alcohols, such as methanol, ethanol, isopropanol, tert-butyl alcohol, esters such
as ethyl acetate, amides such as dimethylformamide, acetic acid, dichloromethane,
toluene, xylene, benzene, pentane, hexane, heptane, petrol ether, 1,4-thioxane, diethyl
ether, diisopropyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxiethane, dimethyl
sulfoxide, or mixtures thereof. In general any solvent susceptible to being used in
a chemical reduction process may be used.
[0039] Said reduction step can be carried out at temperatures that range between -78 °C
and 55 °C, preferably between -10° and 50°C, the preferred temperatures lying between
0°C and 50°C, more preferably between 5°C and 30°C. The reaction time may range from
30 minutes to 2 days, more suitably from 1 hour up to 24 hours. According to a preferred
embodiment, the reduction step is performed using palladium on charcoal suspended
in methanol. In another preferred embodiment, an additional amount of charcoal may
be employed.
[0040] The ratios of equivalents between compound of formula (3'), and hydrogen range from
1:1 to 1:10, respectively. Preferably, the ratio of equivalents between the compound
of formula (3') and the hydrogen is from 1:1 to 1:5, more preferably the ratio is
around 1:3.
Compounds of formula (5)
[0041] Compound of formula (5) is obtained by deprotecting the intermediate of formula (4')
under conventional acidic conditions. Alternatively basic conditions may be applied.
Removal of the amino-protecting-group can be achieved using conditions which will
not affect the remaining portion of the molecule. These methods are well known in
the art and include acid hydrolysis, hydrogenolysis and the like, thus using commonly
known acids in suitable solvents.
[0042] Examples of acids employed in the removal of the amino protecting group include inorganic
acids such as hydrogen chloride, nitric acid, hydrochloric acid, sulfuric acid and
phosphoric acid; organic acids such as acetic acid, trifluoroacetic acid methanesulfonic
acid and p-toluenesulfonic acid; Lewis acids such as boron trifluoride; acidic cationic
ion-exchange resins such as Dowex 50W™. Of these acids, inorganic acids and organic
acids are preferred. Hydrochloric acid, sulfuric acid, phosphoric acid and trifluoroacetic
acid are more preferred, and hydrochloric acid is most preferred.
[0043] The solvent employed during the deprotection of intermediate of formula (4') is not
particularly limited provided that it has no adverse effect on the reaction and dissolves
the starting materials to at least some extent. Suitable solvents are aliphatic hydrocarbons
such as hexane, heptane and petroleum ether; aromatic hydrocarbons such as benzene,
toluene, xylene and mesitylene; halogenated hydrocarbons such as methylene chloride,
chloroform, carbon tetrachloride and dichloroethane; ethers such as diethyl ether,
tetrahydrofuran, 1,4-dioxane and 1,2-dimethoxyethane; alcohols such as methanol, ethanol,
propanol, isopropanol and butanol; esters such as methyl acetate, ethyl acetate, methyl
propionate and ethyl propionate; nitrites such as acetonitrile; amides such as N,N-dimethylformamide
and N,N-dimethylacetamide; sulfoxides such as dimethyl sulfoxide and mixtures thereof.
Aromatic hydrocarbons, alcohols and esters are preferred. Alcohols and water are more
preferred, and water, isopropanol, ethanol and methanol are particularly preferred.
Mixtures of methanol, water, and isopropanol or ethanol, and mixtures of ethanol and
water are also preferred.
[0044] The reaction temperature employed depends upon various factors such as the nature
of the starting materials, solvents and acids. However it is usually between -20°
C and 150° C, and is preferably between 30° C and 100°C, even more preferably at a
temperature of reflux. The reaction time employed depends on the reaction temperature
and the like. It is typically from 5 minutes to 72 hours, and preferably from 15 minutes
to 4 hours.
[0046] As those skilled in the art will recognize, the choice of amino protecting group
employed in a previous step of the process will dictate the reagents and procedures
used in removing said amino protecting group.
[0047] The ratios of equivalents between the compound of formula (3') and the acid in solvent
may range from 1:2 to 1:50, respectively. Preferably, the ratio of equivalents between
the compound of formula (3') and the acid is from 1:2 to 1:8, more preferably the
ratio is around 1:2.
[0048] In a preferred embodiment of the present invention, compound of formula (5) is crystallized.
Crystallization of compound of formula (5) is performed by dissolving compound of
formula (5) in a solvent system, adjusting the pH of the solution and adjusting the
concentration of the compound of formula (5). Alternatively, seed crystals of compound
of formula (5) may be added.
[0049] The solvent system used in the crystallization may comprise one or more water-miscible
solvents and water, or alternatively, the solvent system comprises one or more water-immiscible
solvents and water.
[0050] Examples of water-miscible solvents encompass C1-C4 alcohols such as methanol, ethanol,
n-propanol, isopropanol, n-butanol, isobutanol; cyclic ethers such as tetrahydrofuran
or dioxane; amides such as dimethylformamide, dimethylacetamide, N-methylpyrrolidone;
dimethylsulfoxide, acetonitrile; a mixture of the abovementioned solvents with one
another or a mixture with water; or water itself.
[0051] Examples of water-immiscible solvents are hydrocarbons such as pentane, hexane, cyclohexane,
methylcyclohexane, heptane, toluene, xylene; C4-C8 esters such as methyl formate,
ethyl formate, methyl acetate, ethyl acetate; C4-C8 ethers such as diethyl ether,
tert-butyl methyl ether, isopropyl ether; chlorinated solvents such as methylene chloride,
dichloromethane, chloroform, dichloroethane, chlorobenzene; or a binary or multiple
mixture thereof. When such water-immiscible solvents are used, compound of formula
(5) will be isolated by separation of the organic and aqueous phases.
[0052] Adjustment of concentration of compound of formula (5) may be accomplished by the
addition of water or other suitable solvents, or by evaporation, distillation of the
solvent, or any other equivalent concentrating techniques. In a preferable crystallization,
compound of formula (5) is kept at a concentration between 0.1% and 40% (w/w), preferably
between 1% and 30%, more preferably between 2% and 20%, even more preferably between
4% and 15% w/w.
[0053] Monitoring or in-process control of the values of concentration of compound of formula
(5) in solution may be performed by any method known to the skilled in the art, such
as for example, by HPLC chromatography, measurement of density, titration, and the
like.
[0054] Preferably the solvent used during crystallization of compound of formula (5) is
the same as the solvent used during deprotection of intermediate of formula (4').
Alternatively, when more than one solvent is used, one or more of the solvents used
during crystallization of compound of formula (5), are the same as one or more of
the solvents used during deprotection of intermediate of formula (4').
[0055] Adjustment of the pH of the solution containing compound of formula (5) may be accomplished
by the addition of basic compounds, such as sodium hydroxide, sodium carbonate, potassium
hydroxide, lithium hydroxide, ammonia, hydrazine, calcium hydroxide, methylamine,
ethylamine, aniline, ethylenediamine, triethylamine, tetraethyl ammonium hydroxide,
a C2-C18 amine, a C4 -C18 ammonium hydroxide, sodium methoxide, potassium methoxide,
a C1-C4 organic base, any of the bases listed above, and mixtures thereof. pH of the
solution containing compound of formula (5) will be maintained in the basic range,
preferably at a pH higher than 7, more preferably at a pH higher than 8, and even
more preferably at a pH higher than 9.
[0056] In one embodiment, after addition of the base the suspension is further stirred during
1 hour to 48 hours, preferably during 1 to 10 hours, more preferably during 1 to 5
hours.
[0057] Working temperatures employed during precipitation of compound of formula (5) may
range between -20° and 50°C. Preferably, working temperatures during precipitation
may range between -15°C to 10°C, even more preferably between -10°C and 10°C, most
preferably around 5°C. In another embodiment, compound of formula (5) is collected
by centrifugation and dried in vacuum at around 65°C.
[0058] A preferred crystallized compound of formula (5) is the free base. Alternatively,
other suitable compounds are those crystallized compounds of formula (5) in a salt
form, wherein the salt is selected from hydrochloride, hydrobromide, trifluoroacetate,
fumarate, chloroacetate and methanesulfonate, and the like.
[0059] Intermediates of formula (5) are also active inhibitors of retrovirus proteases.
(3R,3aS,6aR)-hexahydrofuro [2,3-b] furan-3-yl derivate
[0060] (3R,3aS,6aR)-hexahydrofuro [2,3-b] furan-3-ol and precursors thereof, may be synthetised
as described in
WO 03/022853. (3R,3aS,6aR)-hexahydrofuro [2,3-b] furan-3-ol and precursors thereof are suitably
activated with coupling agents to generate a (3R,3aS,6aR)-hexahydrofuro [2,3-b] furan-3-yl
derivate which may undergo carbamoylation with compound of formula (5). Activation
of (3R,3aS,6aR)-hexahydrofuro [2,3-b] furan-3-ol and precursors thereof with the coupling
agent preferably occurs before the coupling with compound of formula (5). Said activation
of (3R,3aS,6aR)-hexahydrofuro [2,3-b] furan-3-ol and precursors thereof and their
coupling to compound of formula (5) has the additional advantage to be a one-pot procedure,
since isolation of the activated intermediate is not necessary.
[0061] Precursors of (3R,3aS,6aR)-hexahydrofuro [2,3-b] furan-3-ol are those compounds where
the oxygen of the alcohol function is protected with O-protecting groups, such as
t-butyl ether ("Boc"), acetates, benzyl groups, benzyl ethers, allyls, silyl protecting
groups such as tert-butyldimethylsilyl (TBS), trimethylsilylethoxymethyl (SEM), alkoxyalkyl
groups such as methoxyethoxymethyl (MEM), methoxymethyl (MOM), tetrahydropyranyl (THP),
tetrahydropyranyl (THE), and the like. Where precursors of (3R,3aS,6aR)-hexahydrofuro
[2,3-b] furan-3-ol are employed, deprotection may be accomplished prior to the coupling
or in situ. Removal of the alcohol protecting groups may be achieved in acidic or
basic conditions, being acidic conditions preferred. Protecting groups are well known
in the art, see for example
Greene, T. W. Protective Groups in Organic Synthesis, John Wiley and Sons, Inc. New
York, 1991.
[0062] Alternatively, (3R,3aS,6aR)-hexahydrofuro [2,3-b] furan-3-ol and precursors thereof
may be obtained through a dynamic diastereoselective resolution of a racemate mixture
of hexahydrofuro [2,3-b] furan-3-ol. In such a case, the racemate mixture is submitted
to the action of certain enzymes such as porcine pancreatic lipase, candida cylindracea,
pancreatin, and the like, in the presence of suitable solvents and reagents such as
acetic anhydride, and vinyl acetate. This alternative route allows the in situ production
of the desired (3R,3aS,6aR)-hexahydrofuro [2,3-b] furan-3-ol enantiomer, which can
be conveniently activated in a one-pot procedure; the undesired stereoisomer is blocked
or rendered inert.
[0063] Examples of coupling agents used in carbamoylation reactions are carbonates such
as bis-(4-nitrophenyl)carbonate, disuccinimidyl carbonate (DSC), carbonyl diimidazole
(CDI). Other coupling agents include chloroformates, such as p-nitrophenylchloroformate,
phosgenes such as phosgene and triphosgene.
[0064] In particular, when the (3R,3aS,6aR)-hexahydrofuro [2,3-b] furan-3-ol is processed
with disuccinimidyl carbonate, 1-([[(3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yloxy]carbonyl]oxy)-2,5-pyrrolidinedione
is obtained. Said compound is a preferred (3R,3aS,6aR)-hexahydrofuro [2,3-b] furan-3-yl
derivate.
[0065] For the activation of the (3R,3aS,6aR)-hexahydrofuro [2,3-b] furan-3-ol and precursors
thereof with a coupling agent it is recommended that the alcohol is present at a concentration
between 1% and 20% (w/w), preferably at a concentration between 2% and 15% (w/w),
more preferably at a concentration between 4% and 10% (w/w).
[0066] Reaction of (3R,3aS,6aR)-hexahydrofuro [2,3-b] furan-3-yl derivate with compound
of formula (5) will be performed in the presence of suitable solvents, such as tetrahydrofuran,
dimethylformamide, acetonitrile, dioxane, dichloromethane or chloroform, and optionally
with bases, such as triethylamine although further cominations from the solvents and
bases hereinabove disclosed are also embodied. Among the solvents, preferred solvents
are aprotic solvents such as tetrahydrofuran, acetonitrile, dimethylformamide, ethyl
acetate, and the like.
[0067] In one embodiment, during the coupling of (3R,3aS,6aR)-hexahydrofuro [2,3-b] furan-3-yl
derivate with compound of formula (5), said derivate is present at a concentration
between 1% and 15% (w/w), preferably at a concentration between 5% and 12% (w/w),
more preferably at a concentration between 8% and 12% (w/w).
[0068] Carbamoylation reaction is suitably carried out at a temperature between -70° and
40°C, preferably between -10°C and 20°C.
[0069] The compound obtained from the coupling of (3R,3aS,6aR)-hexahydrofuro [2,3-b] furan-3-yl
derivate with compound of formula (5) is compound of formula (6). Compound of formula
(6) will preferably be solvated with alcohols such as ethanol, methanol, being the
ethanolate solvate form preferred. Solvation of compound of formula (6) is described
in
PCT/EP03/50176 (Tibotec N.V.), which is incorporated herein by reference.
[0070] In each of the preparations presented above, the reaction products, for instance
compounds of formula (3'), (4'), (5) and the end product compound of formula (6) may
be isolated from the reaction medium and, if necessary, further purified according
to methodologies generally known in the art such as, for example, extraction, crystallization,
distillation, trituration and chromatography.
[0071] For therapeutic use, the salts of the compounds according to the invention, are those
wherein the counter-ion is pharmaceutically or physiologically acceptable. However,
salts having a pharmaceutically unacceptable counterion may also find use, for example,
in the preparation or purification of a pharmaceutically acceptable compound of the
present invention. All salts, whether pharmaceutically acceptable or not are included
within the ambit of the present invention.
[0072] The pharmaceutically acceptable salts of the compounds according to the invention,
i.e. in the form of water-, oil-soluble, or dispersible products, include the conventional
nontoxic salts or the quaternary ammonium salts which are formed, e.g., from inorganic
or organic acids or bases. Examples of such acid addition salts include acetate, adipate,
alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate,
camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate,
fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride,
hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate,
2-naphthalenesulfonate, nicotinate, oxalate, phosphate, pamoate, pectinate, persulfate,
3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate,
tosylate, and undecanoate. Base salts include ammonium salts, alkali metal salts such
as sodium and potassium salts, alkaline earth metal salts such as calcium and magnesium
salts, salts with organic bases such as dicyclohexylamine salts, N-methyl-D-glucamine,
and salts with amino acids such a sarginine, lysine, and so forth. Also, the basic
nitrogen-containing groups may be quaternized with such agents as lower alkyl halides,
such as methyl, ethyl, propyl, and butyl chloride, bromides and iodides; dialkyl sulfates
like dimethyl, diethyl, dibutyl; and diamyl sulfates, long chain halides such as decyl,
lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl halides like
benzyl and phenethyl-bromides and others. Other pharmaceutically acceptable salts
include the sulfate salt ethanolate and sulfate salts.
[0073] The term "polymorphic form" refers to the property of compounds of formula (5) and
(6) to exist in amorphous form, in polymorphic form, in crystalline form with distinct
structures varying in crystal hardness, shape and size. The different crystalline
forms can be detected by crystallographic techniques or indirectly by assessment of
differences in physical and/or chemical properties associated with each particular
polymorph. The different polymorphs vary in physical properties such as solubility,
dissolution, solid-state stability as well as processing behaviour in terms of powder
flow and compaction during tabletting.
[0074] The terms "pseudopolymorphic form" or "solvates" refer to aggregates that consists
of molecules of compound of formula (6) and salts thereof, entrapped or complexed
with solvent molecules, on a mol/mol basis and at various degrees of solvation.
[0075] The intermediates according to the invention may also exist in their tautomeric forms.
Such forms, although not explicitly indicated in the compounds described herein, are
intended to be included within the scope of the present invention.
[0076] Pure stereoisomeric forms of the compounds and intermediates as mentioned herein
are defined as isomers substantially free of other enantiomeric or diastereomeric
forms of the same basic molecular structure of said compounds or intermediates. In
particular, the term "stereoisomerically pure" concerns compounds or intermediates
having a stereoisomeric excess of at least 80% (i. e. minimum 90% of one isomer and
maximum 10% of the other possible isomers) up to a stereoisomeric excess of 100% (i.
e. 100% of one isomer and none of the other), more in particular, compounds or intermediates
having a stereoisomeric excess of 90% up to 100%, even more in particular having a
stereoisomeric excess of 94% up to 100% and most in particular having a stereoisomeric
excess of 97% up to 100%. The terms "enantiomerically pure" and "diastereomerically
pure" should be understood in a similar way, but then having regard to the enantiomeric
excess, respectively the diastereomeric excess of the mixture in question.
[0077] Pure stereoisomeric forms of the compounds and intermediates of this invention may
be obtained by the application of art-known procedures. For instance, enantiomers
may be separated from each other by the selective crystallization of their diastereomeric
salts with optically active acids or bases. Examples thereof are tartaric acid, dibenzoyltartaric
acid, ditoluoyltartaric acid and camphosulfonic acid. Alternatively, enantiomers may
be separated by chromatographic techniques using chiral stationary phases. Said pure
stereochemically isomeric forms may also be derived from the corresponding pure stereochemically
isomeric forms of the appropriate starting materials, provided that the reaction occurs
stereospecifically. Preferably, if a specific stereoisomer is desired, said compound
will be synthesized by stereospecific processes. These processes will advantageously
employ enantiomerically pure starting materials.
[0078] The diastereomeric racemates of the compounds and intermediates of this invention
can be obtained separately by conventional methods. Appropriate physical separation
methods which may advantageously be employed are, for example, selective crystallization
and chromatography, e. g. column chromatography.
[0079] It is clear to a person skilled in the art that the compounds and intermediates of
this invention contain at least two asymmetric centers and thus may exist as different
stereoisomeric forms. These asymmetric centers are indicated with an asterisk (*)
in the figures below.
[0080] The absolute configuration of each asymmetric center that may be present in the compounds
and intermediates of this invention may be indicated by the stereochemical descriptors
R and S, this R and S notation corresponding to the rules described in
Pure Appl. Chem. 1976,45,11-30.
[0081] The present invention is also intended to include all isotopes of atoms occurring
on the present compounds. Isotopes include those atoms having the same atomic number
but different mass numbers. By way of general example and without limitation, isotopes
of hydrogen include tritium and deuterium. Isotopes of carbon include C-13 and C-14.
[0082] The reagents and solvents used throughout the specification may be replaced by functional
alternatives or functional derivatives thereof as they are known to a person skilled
in the art. Also the reaction conditions such as stirring times, purification and
temperature may be adjusted to optimise reaction conditions. Similarly, the reaction
products may be isolated from the medium and, if necessary, further purified according
to methodologies generally known in the art such as, for example, extraction, crystallization,
trituration and chromatography. A number of intermediates and starting materials used
in the foregoing preparations are known compounds, while others may be prepared according
to methods known in the art of preparing said or similar compounds.
[0083] The compounds of formula (5) and all intermediates leading to the formation of stereoisomerically
pure compounds are of particular interest in preparing 4-aminobenzene sulfonamide
compounds, as HIV protease inhibitors, as disclosed in
WO 95/06030,
WO 96/22287,
WO 96/28418,
WO 96/28463,
WO 96/28464,
WO 96/28465 WO 97/18205, and
WO 02/092595 all incorporated herein by reference, and in particular, the HIV-protease inhibitor
compound of formula (6), and any addition salt, polymorphic and/or pseudopolymorphic
forms thereof.
[0084] Thus, the present invention also relates to HIV protease inhibitors such as compound
of formula (6) and any pharmaceutically acceptable salt, polymorphic or pseudopolymorphic
form thereof, obtained by using any intermediate as described hrerein, wherein both,
intermediates and compound of formula (6), are prepared as described in the present
invention.
[0085] Thus, the present invention also relates to HIV protease inhibitors such as compound
of formula (6) and any pharmaceutically acceptable salt, polymorphic or pseudopolymorphic
form thereof, obtained by using a compound of formula (5) as intermediate, wherein
both compound of formula (5) and compound of formula (6) are prepared as described
in the present invention.
[0086] The following examples are meant to illustrate the present invention. The examples
are presented to exemplify the invention and are not to be considered as limiting
the scope of the invention as defined by the appended claims.
Examples
Example 1: Preparation of (1-Benzyl-2-hydroxy-3-isobutylamino-propyl)-carbamic acid
tert-butyl ester
[0087] To 154.4 Kg isobutylamine, (1-Oxiranyl-2-phenyl-ethyl)-carbamic acid tert-butyl ester
(53.3 Kg) was added, and then the solution was heated under reflux. Under reduced
pressure, isobutylamine was removed from the reaction mixture, and then replaced by
toluene.
Example 2: Preparation of (1-Benzyl-2-hydroxy-3-[isobutyl-(4-nitro-benzenesulfonyl)-amino]-propyl}-carbamic
acid tert-butyl ester
[0088] 26.7 kg triethylamine were added to the prepared solution in Example 1, and the obtained
solution was heated to 82-88°C. To the solution, a solution of 4-nitrobenzenesulfonyl
chloride (53 Kg) in toluene was gradually added and stirred. The obtained reaction
mixture was washed with water.
The washed solution of (1-Benzyl-2-hydroxy-3-[isobutyl-(4-nitro-benzenesulfonyl)-amino]-propyl)-carbamic
acid tert-butyl ester was heated, then toluene and n-heptane were added. This solution
was cooled and seeded with crystals of (1-Benzyl-2-hydroxy-3-[isobutyl-(4-nitro-benzenesulfonyl)-amino]-propyl)-carbamic
acid tert-butyl ester. After the deposition of crystals was observed, the solution
was kept stirring and then was slowly cooled to 20-30°C. The resulting crystals were
filtered off and washed with a mixed solution composed of toluene and n-heptane to
give the wet crystals of (1-Benzyl-2-hydroxy-3-[isobutyl-(4-nitro-benzenesulfonyl)-amino]-propyl)-carbamic
acid tert-butyl ester (yield 87-91%, based on (1-Oxiranyl-2-phenyl-ethyl)-carbamic
acid tert-butyl ester).
Example 3: Preparation of (1-Benzyl-2-hydroxy-3-[isobutyl-(4-aminobenzenesulfonyl)-amino]-propyl)-carbamic
acid tert-butyl ester
[0089] The wet crystals of (1-Benzyl-2-hydroxy-3-[isobutyl-(4-nitro-benzenesulfonyl)-amino]-propyl)-carbamic
acid tert-butyl ester were suspended in ethanol (around 950 L), and then hydrogenated
in the presence of 10 wt% palladium carbon at around 5-30°C. After the resulting reaction
mixture was filtered to remove the palladium-carbon, the filtrate was concentrated
under reduced pressure to give a solution of (1-Benzyl-2-hydroxy-3-[isobutyl-(4-amino-benzenesulfonyl)-amino]-propyl)-carbamic
acid tert-butyl ester in ethanol.
Example 4: Preparation of 4-Amino-N-(2R, 3S) (3-amino-2-hydroxy-4-phenyl-butyl)-N-isobutyl-benzenesulfonamide
[0090] The solution of (1-Benzyl-2-hydroxy-3-[isobutyl-(4-amino-benzenesulfonyl)-amino]-propyl)-carbamic
acid tert-butyl ester obtained in Example 3 was heated for reflux, and then concentrated
hydrochloric acid (35-37 kg) was added. The solution was stirred.
[0091] The obtained solution was then cooled to 40±3°C followed by the addition of water.
Adjustment of the pH of the solution to around 9.5 with aqueous solution of sodium
hydroxide gave crystals of 4-Amino-N-(3-amino-2-hydroxy-4-phenyl-butyl)-N-isobutyl-benzenesulfonamide.
Additional water was added to this solution to adjust the concentration of 4-Amino-N-(3-amino-2-hydroxy-4-phenyl-butyl)-N-isobutylbenzenesulfonamide
to 5.5-5.8 wt%, and then this solution was cooled to 6 ± 4°C. The resulting crystals
were filtered off and washed with a mixed solution composed of water and ethanol and
then washed with water. The resulting wet crystals were subjected to vacuum drying
to give the product of (2R,3S)-N-(3-amino-2-hydroxy-4-phenylbutyl)-N-isobutyl-4-amino-benzenesulfonamide.
Yields were 75∼85% based on (1-Benzyl-2-hydroxy-3-[isobutyl-(4-nitro-benzenesulfonyl)-amino]-propyl)-carbamic
acid tert-butyl ester.
Example 5: Preparation of 4-Amino-N-((2R,3S)-3-amino-2-hydroxy-4-phenylbutyl)-N-(isobutyl)benzene
sulfonamide
[0092] 50,00 g of (1-Benzyl-2-hydroxy-3-[isobutyl-(4-nitro-benzenesulfonyl)-amino]-propyl)-carbamic
acid tert-butyl ester, which was prepared according to the procedures described in
WO99/48885,
WO01/12599, and
WO01/46120; 2 mol% of ethanolamine and palladium on activated charcoal were suspended in methanol,
rendered inert and evacuated. At an inside temperature of 22-30°C about 3,0 eq of
hydrogen were added at overpressure. Then the catalyst was removed by filtration.
The colorless (to slightly yellowish) solution was treated with 21.70 g hydrochloric
acid 37% and heated to reflux for 2 h. After complete conversion methanol was removed
by distillation. The precipitation was performed in a mixture of the solvents MeOH/Water/IPA-mixture
1:8:6,5. At a temperature of 0-7°C, sodium hydroxide 30% was dosed until a pH value
of pH> 12.5 was reached. After 4 to 48 h the white precipitate was filtered and washed
with water and isopropanol. The wet product was dried in vacuum at 65°C. The process
yielded 36,94 g of a white to yellowish powder.
Example 6: Preparation of 4-Amino-N-((2R,3S)-3-amino-2-hydroxy-4-phenylbutyl)-N-isobutyl)benzene
sulfonamide
[0093] 50,00 g of (1-Benzyl-2-hydroxy-3-[isobutyl-(4-nitro-benzenesulfonyl)-amino]-propyl)-carbamic
acid tert-butyl ester, which was prepared according to the procedures described in
WO99/48885,
WO01/12599, and
WO01/46120; and palladium on activated charcoal were suspended in ethanol, rendered inert and
evacuated. At an inside temperature of 22-30°C about 3,0 eq of hydrogen were added
at overpressure. Then the catalyst was removed by filtration. After distillation of
the alcohol (1-Benzyl-2-hydroxy-3-[isobutyl-(4-amino-benzenesulfonyl)-amino]-propyl)-carbamic
acid tert-butyl ester remained as a colorless foam in a yield of 97%. (1-Benzyl-2-hydroxy-3-[isobutyl-(4-amino-benzenesulfonyl)-amino]-propyl)-carbamic
acid tert-butyl ester was dissolved in methanol treated with 21.70 g hydrochloric
acid 37% and heated to reflux for 2 h. After complete conversion most of the alcohol
was removed by distillation. The hydrochloric salt of 4-Amino-N-((2R,3S)-3-amino-2-hydroxy-4-phenylbutyl)-N-isobutyl)benzene
sulfonamide was precipitated by removing most of the alcohol by distillation and adding
dichloromethane to the 40°C warm solution. By stirring and cooling to room temperature
the hydrochloric salt precipitated immediately. The precipitation of 4-Amino-N-((2R,3S)-3-amino-2-hydroxy-4-phenylbutyl)-N-isobutyl)benzene
sulfonamide was performed by dissolving the hydrochloric salt in a mixture of the
solvents EtOH/water -mixture 1:1. At a temperature of 0-7°C, sodium hydroxide 30%
was dosed until a pH value of pH> 12.5 was reached. After 4 to 48 h the white precipitate
was filtered and washed with water and dried in vacuum. The process yielded 33,78
g of a white to yellowish powder.
Example 7: Preparation of (3R,3aS,6aR)-hexahydrofuro [2,3-b] furan-3-yl(1S,2R)-3-[[(4-aminophenyl)
sulfonyl] (isobutyl) amino]-1-benzyl-2-hydroxypropylcarbamate ethanolate
[0094] 100 mmol (3R,3aS,6aR)-hexahydrofuro [2,3-b] furan-3-ol in ethyl acetate were added
onto 120 mmol of disuccimidylcarbonate (95%) in acetonitrile. Following, a solution
of 140 mmol triethylamine in ethylacetate was added and stirred. The mixture was cooled
and treated with a suspension of 92 mmol of 4-Amino-N-((2R,3S)-3-amino-2-hydroxy-4-phenylbutyl)-N-(isobutyl)benzene
sulfonamide in ethyl acetate. 20 mmol methylamine, 41% aqueous solution in ethanol
were added and the mixture was warmed. The reaction was washed twice with 10% Na
2CO
3-solution and with water. Solvent was evaporated and ethanol was added. Another portion
of solvent was distilled off. The temperature was kept around 40 - 45 ° C and crystallization
was initiated by seeding. After stirring the mixture was cooled, stirred for another
90 min stirred, cooled and again stirred for 60 min. The precipitate was filtered
and washed with ethanol. The wet product was dried in vacuo at 40 °C. 43.5 g of (3R,3aS,6aR)-hexahydrofuro
[2,3-b] furan-3-yl (1S,2R)-3-[[(4-aminophenyl) sulfonyl] (isobutyl) amino]-1-benzyl-2-hydroxypropylcarbamate
were suspended in ethanol abs. and dissolved. The clear solution was cooled and seeding
was applied. Crystallization occurred while cooling the mixture. Stirring was continued
for another 60 min, followed by cooling, stirring and filtering off the product, which
was washed with cold ethanol abs. The wet product was dried in vacuo at 40 °C. Yield:
42.1 g = 71 %.
Example 8: Preparation of (3R,3aS,6aR)-hexahydrofuro [2,3-b] furan-3-yl (1S,2R)-3-[[(4-aminophenyl)
sulfonyl] (isobutyl) amino]-1-benzyl-2-hydroxypropylcarbamate ethanolate
[0095] 100 mmol (3R,3aS,6aR)-hexahydrofuro [2,3-b] furan-3-ol in ethyl acetate were added
onto 105 mmol of bis-(4-nitrophenyl)carbonate in acetonitrile. Following, a solution
of 250 mmol triethylamine in ethylacetate was added and stirred. The mixture was treated
with a suspension of 95 mmol of 4-Amino-N-((2R,3S)-3-amino-2-hydroxy-4-phenylbutyl)-N-(isobutyl)benzene
sulfonamide in ethyl acetate. 20 mmol methylamine, 41% aqueous solution in ethanol
were added. The reaction was washed three times with 10% K
2CO
3-solution and with water. Solvent was evaporated and ethanol was added. Another portion
of solvent was distilled off. The temperature was kept around 40 - 45 ° C and crystallization
was initiated by seeding. After stirring the mixture was cooled, stirred for another
90 min stirred, cooled and again stirred for 60 min. The precipitate was filtered
and washed with ethanol. The wet product was dried in vacuo at 40 °C. 43.5 g of (3R,3aS,6aR)-hexahydrofuro
[2,3-b] furan-3-yl (1S,2R)-3-[[(4-aminophenyl) sulfonyl] (isobutyl) amino]-1-benzyl-2-hydroxypropylcarbamate
were suspended in ethanol abs. and dissolved. The clear solution was cooled and seeding
was applied. Crystallization occurred while cooling the mixture. Stirring was continued
for another 60 min, followed by cooling, stirring and filtering off the product, which
was washed with cold ethanol abs. The wet product was dried in vacuo at 40 °C. Yield:
47.9 g = 81 %.
Example 9: Preparation of (3R,3aS,6aR)-hexahydrofuro [2,3-b] furan-3-yl(1S,2R)-3-[[(4-aminophenyl)
sulfonyl] (isobutyl) amino]-1-benzyl-2-hydroxypropylcarbamate ethanolate
[0096] 100 mmol (3R,3aS,6aR)-hexahydrofuro [2,3-b] furan-3-ol in acetonitrile were added
onto 110 mmol of disuccimidylcarbonate (95%) in acetonitrile. Following 300 mmol pyridine
was added and stirred. The mixture was cooled and treated with a suspension of 95
mmol of 4-Amino-N-((2R,3S)-3-amino-2-hydroxy-4-phenylbutyl)-N-(isobutyl)-benzene sulfonamide
in acetonitrile, followed by 100 mmol of triethylamine. 20 mmol methylamine, 41% aqueous
solution in water were added and the mixture was warmed. 80 g solvent were distilled
off, MTBE was added and the reaction mixture was washed with 10% Na
2CO
3-solution, with a mixture of sodium sulfate in sulfuric acid and again with 10% Na
2CO
3-solution. Solvent was evaporated and ethanol was added. Another portion of solvent
was distilled off. The temperature was kept around 40 - 45 ° C and crystallization
was initiated by seeding. After stirring the mixture was cooled, stirred for another
90 min stirred, cooled and again stirred for 60 min. The precipitate was filtered
and washed with ethanol. The wet product was dried in vacuo at 40 °C. 43.5 g of (3R,3aS,6aR)-hexahydrofuro
[2,3-b] furan-3-yl (1S,2R)-3-[[(4-aminophenyl) sulfonyl] (isobutyl) amino]-1-benzyl-2-hydroxypropylcarbamate
were suspended in ethanol abs. and dissolved. The clear solution was cooled and seeding
was applied. Crystallization occurred while cooling the mixture. Stirring was continued
for another 60 min, followed by cooling, stirring and filtering off the product, which
was washed with cold ethanol abs. The wet product was dried in vacuo at 40 °C. Yield:
48.1 g = 81 %.